Saturday, October 1, 2022
Mitochondrial Health Optimal Health

#180 – AMA #28: All things testosterone and testosterone replacement therapy

In this “Ask Me Anything” (AMA) episode, Peter and Bob discuss all things related to testosterone: what happens when testosterone levels are low, and the potential benefits and risks of testosterone replacement therapy (TRT). They explain the physiology of testosterone, how it works, and how its level changes over the course of a person’s life. They have a detailed discussion about existing literature, which reveals vast potential structural, functional, and metabolic benefits of testosterone replacement therapy. They also take a very close look at potential risks of this therapy, with a focus on the controversial effects on cardiovascular disease and prostate cancer.

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We discuss:

  • A primer on the hormone testosterone and how it influences gene expression [3:30];
  • How the body naturally regulates testosterone levels [11:30];
  • The defining threshold for “low testosterone,” how low T impacts men, and why free testosterone is the most important metric [16:15];
  • When it makes sense to treat low testosterone [26:00];
  • The structural and metabolic benefits of testosterone replacement therapy [29:15];  
  • Body composition changes with TRT [45:30];
  • Changes in bone mineral density with TRT [48:15];
  • The metabolic impact of TRT: glucose, insulin, triglycerides, and more [52:30];
  • A study investigating testosterone replacement therapy for prevention or reversal of type 2 diabetes [59:30];
  • The impact of TRT on metabolic parameters and body composition—A study comparing results from continuous vs. interrupted treatment [1:07:15];  
  • The controversy over TRT and cardiovascular disease [1:21:45];
  • Two flawed studies that shaped perceptions of risks associated with TRT [1:44:15];
  • The controversy over TRT and prostate cancer [1:56:45];
  • Other potential risks with testosterone replacement therapy [2:02:15]; and 
  • More


A primer on the hormone testosterone and how it influences gene expression [3:30]


  • Testosterone is a steroid hormone
  • It’s derived from the cholesterol family and it is synthesized in a number of steps
  • What’s really important is that it exerts its effect through binding to an androgen receptor
  • Because it is a hydrophobic molecule, it basically makes its way into the cell easily—meaning it doesn’t require a channel or a receptor on the cell membrane to make its way inside
  • Cholesterol can’t make its way through the bloodstream the way glucose can or the way electrolytes can; for example, sodium & potassium (because electrolytes are soluble in water, they’re therefore soluble in the bloodstream (plasma), and they don’t need a chaperone or carrier proteins)
  • But cholesterol does need carrier proteins (lipoproteins)
  • Similarly, testosterone needs to be bound primarily to carrier proteins

Two dominant carrier proteins for testosterone:

  • 1) One is called sex hormone-binding globulin or SHBG 
  • 2) The other is albumin
  • SHBG is responsible for about two-thirds of the carrying capacity, whereas albumin is about one-third
  • what’s important is knowing that it’s only the unbound portion of testosterone that is able to actually exert the biological influence
  • “We pay very special attention to how much testosterone is “free,” and free is defined as the testosterone that is neither bound to SHBG or albumin”
  • whereas there’s another term that many people who have had a blood test may notice, something called bioavailable testosterone
    • that’s the portion that is unbound to SHBG, but remains bound to albumin or is free
  • In other words, free testosterone, which is a tiny amount, it’s typically 1% to 3% of total testosterone, is that which is completely unbound
  • whereas bioavailable includes that tiny fraction plus the much larger fraction that is bound to albumin
  • From a clinical standpoint, symptoms track more with free testosterone than bioavailable
  • But honestly, they’re close enough in terms of their prediction of what’s going on that if you’re using a lab that relies on one versus the other, it’s probably okay.
  • The lab that Peter uses looks at total testosterone, of course, but free testosterone, and it’s really the free number that Peter is paying most attention to

How testosterone works [9:15]

  • It makes its way into the cell, and then it binds to an androgen receptor (this receptor is outside of the nucleus)
  • It undergoes this conformational change, and it causes things called heat shock proteins to be dislocated
  • Heat shock proteins get transported into the cell, and then something called the dimerization takes place 
  • Dimerization is a fancy way of saying a new molecule is created by the fusion—and it doesn’t have to be covalent, it can be non-covalent—but fusion of two molecules that look very much alike
  • This androgen receptor dimer now makes its way into the nucleus and binds with something called a hormone response element, which is what actually turns on and off gene transcription
  • Effectively, testosterone is up or downregulating genes that are responsible for a number of things—the most obvious of these are the anabolic or growth characteristics

Another important hormone worth mentioning is dihydrotestosterone (DHT)

  • DHT is about three to six times more powerful than testosterone—meaning a greater binding affinity for the androgen receptor
  • DHT is something that is converted from testosterone using an enzyme called 5-alpha reductase
  • We could go a lot deeper into it, but I’m not sure it really adds much value to the clinical questions that we’re going to want to get to

{end of show notes preview}

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